Micro<scp>RNA</scp>‐146a represses <scp>LRP</scp>2 translation and leads to cell apoptosis in Alzheimer's disease

Zhang, Bei; Wang, Liling; Ren, Rong; Dammer, Eric B.; Zhang, Yongfang; Huang, Yue; Chen, Shengdi; Wang, Gang

doi:10.1002/1873-3468.12229

Cited by 35 publications

(34 citation statements)

References 49 publications

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“…The reduced levels of TNF-RI, TNF-RII, and CCL2 may reflect differential expression by different cells in the demyelinating corpus callosum, and this can influence the ultimate protective versus detrimental effect; the observed protection from CPZ-induced demyelination is a combinatory effect of miR-146a deficiency in all cell types, and we cannot exclude the possibility that lack of miR-146a in particular cell types could be harmful. We hypothesize that pro-apoptotic properties of miR-146a ( 23 , 24 , 32 , 64 ) may also contribute to decreased demyelination, increased number of myelinating oligodendrocytes and reduced axonal loss during the demyelination phase induced by CPZ in KO mice.…”

Section: Discussionmentioning

confidence: 99%

“…miR-146a is involved in a negative feedback loop: it is induced by NF-kB, but also inhibits the activation of NF-κB ( 22 ). miR-146a is involved in cell death and survival; in glioma cells: overexpression of miR-146a suppressed cell survival, proliferation, and migration, whereas inhibition resulted in improved migration potential ( 23 , 24 ). miR-146a amplified the effect of a G-actin-sequestering peptide to promote OPC differentiation in vitro , and its overexpression in neural progenitor cells increased their differentiation into OPCs ( 25 , 26 ).…”

Section: Introductionmentioning

confidence: 99%

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Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice

et al. 2018

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BackgroundThe cuprizone (CPZ) model of multiple sclerosis (MS) was used to identify microRNAs (miRNAs) related to in vivo de- and remyelination. We further investigated the role of miR-146a in miR-146a-deficient (KO) mice: this miRNA is differentially expressed in MS lesions and promotes differentiation of oligodendrocyte precursor cells (OPCs) during remyelination, but its role has not been examined during demyelination.MethodsMicroRNAs were examined by Agilent Mouse miRNA Microarray in the corpus callosum during CPZ-induced demyelination and remyelination. Demyelination, axonal loss, changes in number of oligodendrocytes, OPCs, and macrophages/microglia was compared by histology/immunohistochemistry between KO and WT mice. Differential expression of target genes and proteins of miR-146a was analyzed in the transcriptome (4 × 44K Agilent Whole Mouse Genome Microarray) and proteome (liquid chromatography tandem mass spectrometry) of CPZ-induced de- and remyelination in WT mice. Levels of proinflammatory molecules in the corpus callosum were compared in WT versus KO mice by Meso Scale Discovery multiplex protein analysis.ResultsmiR-146a was increasingly upregulated during CPZ-induced de- and remyelination. The absence of miR-146a in KO mice protected against demyelination, axonal loss, body weight loss, and atrophy of thymus and spleen. The number of CNP+ oligodendrocytes was increased during demyelination in the miR-146a KO mice, while there was a trend of increased number of NG2+ OPCs in the WT mice. miR-146a target genes, SNAP25 and SMAD4, were downregulated in the proteome of demyelinating corpus callosum in WT mice. Higher levels of SNAP25 were measured by ELISA in the corpus callosum of miR-146a KO mice, but there was no difference between KO and WT mice during demyelination. Multiplex protein analysis of the corpus callosum lysate revealed upregulated TNF-RI, TNF-RII, and CCL2 in the WT mice in contrast to KO mice. The number of Mac3+ and Iba1+ macrophages/microglia was reduced in the demyelinating corpus callosum of the KO mice.ConclusionDuring demyelination, absence of miR-146a reduced inflammatory responses, demyelination, axonal loss, the number of infiltrating macrophages, and increased the number of myelinating oligodendrocytes. The number of OPCs was slightly higher in the WT mice during remyelination, indicating a complex role of miR-146a during in vivo de- and remyelination.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice

et al. 2018

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“…Other factors affecting megalin expression cannot be excluded, including the possible effects of other miRNAs not examined in the present study. MiR-146a was previously shown to target megalin in brain to increase cell apoptosis in Alzheimer’s disease [ 41 ]. Differences in cell signaling pathways may account for this apparent discrepancy between brain and kidney.…”

Section: Discussionmentioning

confidence: 99%

Renal miR-148b is associated with megalin down-regulation in IgA nephropathy

et al. 2018

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Megalin is essential for proximal tubule reabsorption of filtered proteins, hormones, and vitamins, and its dysfunction has been reported in IgA nephropathy (IgAN). miR-148b has been shown to regulate renal megalin expression in vitro and in animal models of kidney disease. We examined a potential role of miR-148b and other miRNAs in regulating megalin expression in IgAN by analyzing the association between megalin and miR-148b, miR-21, miR-146a, and miR-192 expression. Quantitative PCR (qPCR) analysis identified a marked increase in renal levels of several miRNAs, including miR-148b, miR-21, miR-146a, and a significant decrease in megalin mRNA levels in IgAN patients when compared with normal controls. By multiple linear regression analysis, however, only renal miR-148b was independently associated with megalin mRNA levels in IgAN. Proximal tubule megalin expression was further evaluated by immunofluorescence labeling of biopsies from the patients. The megalin expression was significantly lower in patients with highest levels of renal miR-148b compared with patients with lowest levels. To examine the direct effects of the miRNAs on megalin and other membrane proteins expression, proximal tubule LLC-PK1 cells were transfected with miR-148b, miR-21, miR-146a, or miR-192 mimics. Transfection with miR-148b mimic, but not the other three miRNA mimics inhibited endogenous megalin mRNA expression. No significant effect of any of the four miRNA mimics was observed on cubilin or aquaporin 1 (AQP1) mRNA expression. The findings suggest that miR-148b negatively regulates megalin expression in IgAN, which may affect renal uptake and metabolism of essential substances.

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“…The negative correlation of KRAS and YY1 knockdown suggest the potential regulation between YY1 and miR-146a. Moreover, miR-146a induced cell apoptosis in PCa cells by activating cleaved caspase-3 (15). Collectively, these results indicated that YY1 depletion induced cell apoptosis of PCa at least in a miR-146a-assisted manner.…”

Section: Resultsmentioning

confidence: 99%

Upregulation of miR-146a by YY1 depletion correlates with delayed progression of prostate cancer

Huang

Tao

Liu

et al. 2017

International Journal of Oncology

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Previously published studies explained that the excessive expression of miR-146a influences the prostate cancer (PCa) cells in terms of apoptosis, progression, and viability. Although miR-146a acts as a tumor suppressor, current knowledge on the molecular mechanisms that controls its expression in PCa is limited. In this study, gene set enrichment analysis (GSEA) showed negatively enriched expression of miR-146a target gene sets and positively enriched expression of gene sets suppressed by the enhancer of zeste homolog 2 (EZH2) after YY1 depletion in PCa cells. The current results demonstrated that the miR-146a levels in PCa tissues with high Gleason scores (>7) are significantly lower than those in PCa tissues with low Gleason scores (≤7), which were initially observed in the clinical specimens. An inverse relationship between YY1 and miR-146a expression was also observed. Experiments indicated the decrease in cell viability, proliferation, and promoting apoptosis after YY1 depletion, while through inhibiting miR-146a could alleviate the negative effect brought by YY1 depletion. We detected the reversed adjustment of YY1 to accommodate miR-146a transcriptions. On the basis of YY1 depletion, we determined that the expression of miR-146a increased after EZH2 knockdown. We validated the combination of YY1 and its interaction with EZH2 at the miR-146a promoter binding site, thereby prohibiting the transcriptional activity of miR-146a in PCa cells. Our results suggested that YY1 depletion repressed PCa cell viability and proliferation and induced apoptosis at least in a miR-146a-assisted manner.

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MicroRNA‐146a represses LRP2 translation and leads to cell apoptosis in Alzheimer's disease

Cited by 35 publications

References 49 publications

Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice

Experimental Demyelination and Axonal Loss Are Reduced in MicroRNA-146a Deficient Mice

Renal miR-148b is associated with megalin down-regulation in IgA nephropathy

Upregulation of miR-146a by YY1 depletion correlates with delayed progression of prostate cancer

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